This invention relates to compositions that are useful in medical applications intended to provide for integration with and subsequent attachment to the surrounding mammalian tissue. A requirement for any medical device that is to become well integrated with the surrounding host tissue is an open structure on the surface of the implant that is sufficiently large for cells to readily penetrate. If the open structure is sufficiently large to allow for the ingrowth of both collagenous and vascular tissues, a well tolerated attachment between the implant and the surrounding tissue is then possible.
Porous structures for implantable devices sufficiently large to allow ingrowth and attachment of tissue can be achieved through a variety of means. Various technologies are able to deliver tailored open-celled structures with various pore sizes to fit the particular cell ingrowth applications. Use of expanded polymeric membrane materials, such as expanded polytetrafluoroethylene (e-PTFE) is one such technique. It can be tailored to provide optimal tissue integration. It is considered chemically inert and therefore possesses enhanced biocompatibility.
The use of extruded fibers or filaments and their subsequent assembly into a variety of organized structures is common. These structures fall into the categories of traditional weaving and knitting. Such weave and knit technologies can be found in various "meshes" found under the trade names of Vicryl.RTM., Dexon.RTM., and Proline.RTM. meshes. The resulting structural integrity is primarily due to the alignment of the component fibers into bundles, which are then weaved or knitted into the particular desired construction. Besides the high cost and complexity of the knitting and weaving equipment, a particular additional drawback of such construction is an increased potential for colonization and wicking of bacteria within the interstices of the aligned fiber bundles if the implant becomes contaminated.
Another method of assembling fibers is as a non-woven fibrous construction. This construction involves a random arrangement of fibers or filaments rather than the organized fibrous construction which typifies weaves and knits. The random nature of the non-wovens structure makes manufacturing of the fabric easier than weaves and knits. However, few fibrous implants utilize non-woven constructions since the mechanical interlocking between fibers in such webs are generally weak. Consequently only limited applications such as felts and pledgets exist for the non-woven implantables that are dependent on fiber entanglement for their mechanical integrity; these possess relatively poor cohesive or tensile strength. Non-woven strength can be added by the addition of a subsequent binding process which produces an attachment of the randomly deposited fibers at their points of contact. One of the few non-woven implantables on the market is Resolut.RTM. Regenerative Material which is disclosed in PCT #WO92/10218 and is composed of staple fibers and an adhesive binder to produce its bioresorbable non-woven structure.
Bioresorbable materials are particularly desirable for use in many medical applications, especially in implant applications, controlled release, and cell growth tissue engineering applications. Most implantable bioresorbable materials are used either in the form of sutures or in the controlled delivery of drugs or other bioactive agents. In the case of sutures or other structures which bear mechanical loads during at least part of their implantation, semi-crystalline polymer systems are utilized. Conversely, controlled release applications where no mechanical loading is required typically utilize amorphous polymer systems for their consistent diffusion properties.
A useful implant application for a non-woven construction is as a barrier material in mammalian tissue regeneration, also known as guided tissue regeneration (GTR). In one such GTR application, either a non-resorbable or bioresorbable membrane can be employed to separate an area where bone growth is desirable from adjacent areas where competing faster growing gingival tissue may be present. The implanted GTR membrane is used as a protective cover and acts as a barrier to entry by the other tissues into the space where bone growth is desired. Simultaneously the barrier must also resist collapsing into the defect under the pressure of the overlying tissues. The advantage of a bioresorbable material is that once its primary purpose is achieved it will be absorbed, thus eliminating any surgical need to remove it.
The preservation of space between the surface of the defect and the desired contours of the subsequently regenerated surface is necessary in order to allow for the regeneration of tissues into that space. Periodontal structures which may be regenerated in this fashion are the periodontal ligament, bone and cementum. The barrier material allows propagation of bone and periodontal ligament cells by precluding entry of epithelial cells and gingival connective tissue cells into the provided space.
One commercially available material that provides a cell-barrier for periodontal guided tissue regeneration is GORE-TEX.RTM. Periodontal Material. This is an expanded polytetrafluoroethylene (e-PTFE) material that serves as a cell-barrier between the gingiva and a periodontal defect and is intended to preserve the necessary space between the surface of the defect and the desired contours of the subsequently regenerated surface. This material is made of porous expanded PTFE having a microstructure of nodes interconnected by fine fibrils. One portion of the total surface area of the GORE-TEX Periodontal Material has a porous structural surface that becomes infiltrated with blood clot and ingrown with fibrous connective tissue, thereby inhibiting epithelial migration. The remaining portion of the surface area has a cell-barrier structure of low porosity for isolating the overlying gingival connective tissue from the underlying defect. It is not bioresorbable, however, and must be removed in a subsequent surgical procedure.
Another commercially available cell barrier sheet material intended for guided tissue regeneration is the previously mentioned Resolut.RTM. Regenerative Material, also from W. L. Gore & Associates, Inc. PCT application #WO09/10218 describes this material as a bioabsorbable material made of a non-woven fibrous matrix of polyglycolic acid fibers laminarly affixed to a cell-barrier sheet material that is a copolymer of polylactic acid and polyglycolic acid. The overall material is intended to provide sufficient rigidity in vivo to maintain space over the defect as it regenerates.
There have been other attempts to produce suitable surgical barriers from bioresorbable materials. A 70 micron thick solvent-cast bioresorbable polylactic acid membrane having no inherent porosity or tissue cell permeability was tested in periodontal applications as a cell-barrier material for exclusion of epithelium and gingival connective tissue during healing (I. Magnusson, et al., "New Attachment Formations Following Controlled Tissue Regeneration Using Biodegradable Membranes", J. Periodontal, January 1988, pp. 1-6). Tests showed some new formation of cementum and bone. Reproductions of this material demonstrated poor surgical handling characteristics due to its thin friable construction and also proved to be difficult to suture because of its brittleness. This material makes no provision for tissue ingrowth on either of its surfaces.
Another commercially available material for use in guided or controlled tissue regeneration is Vicryl.RTM. Periodontal Mesh available from Johnson & Johnson. The Vicryl Periodontal Mesh is comprised of woven fibers made from a bioresorbable copolymer of about 90% glycolide and 10% lactide. Studies have shown that the Vicryl Periodontal Mesh has had some success as a barrier material that provides for tissue regeneration (Fleisher, et al., "Regeneration of Lost Attachment Apparatus in the Dog Using Vicryl Absorbable Mesh", International Journal of Periodontics and Restorative Dentistry, 2/1988, pp. 45-55). This material is a single layer material of woven construction that is intended to both promote tissue ingrowth and simultaneously serve as a tissue barrier. As these are somewhat contradictory objectives for a single layer material of woven construction having a degree of inherent porosity, ingrowth can only be made to occur at the expense of the barrier function. The effectiveness of this material is therefore a compromise between the material's ability to allow for tissue ingrowth and the requirement to simultaneously function as a tissue barrier. An additional difficulty with this conventional woven construction is its lack of adequate rigidity and a resulting inferior ability to maintain space adjacent to the defect.
While most of the preceding guided tissue regeneration bioresorbable designs utilize readily available polymers and copolymers derived from glycolic and lactic acids, a particular polymer which provides both sufficient in vivo rigidity and longevity to resist its collapse into a defect is described in U.S. Pat. No. 4,243,775 to Rosensaft, et al and in U.S. Pat. No. 4,300,565. The disclosed material is a block copolymer of glycolide (PGA) and either lactide (PLA) or trimethylene carbonate (TMC) that is described as useful for absorbable articles such as sutures. The specific block copolymer combination of PGA:TMC has been used extensively as commercially available surgical sutures produced and marketed by Davis & Geck under the trade name of Maxon.RTM.. This same polymer system has been utilized to produce a non-porous structure for the repair and regeneration of bone that is disclosed in U.S. Pat. No. 5,080,655 issued to Jarret, et al. The disclosure describes an absorbable deformable surgical device fabricated from the same PGA:TMC copolymers described within Rosensaft (U.S. Pat. No. 4,243,775) and Casey (U.S. Pat. No. 4,429,080). None of these refer to embodiments that can be described as non-woven fibrous structures. Other bioresorbable block copolymer systems which are of potential relevance to this invention are described within U.S. Pat. Nos. 4,916,193 and 4,920,203.
Besides planar porous materials, it is additionally desirable in some implantable applications to deliver a porous three dimensional object for the function of filling a particular space, rather than for covering it as has been described above. Filling of a defect with a porous biomaterial is a common approach toward treating bone defects. In such applications open celled bioresorbable foams are common, however these materials generally possess limited tensile strength since it is relatively difficult to introduce molecular alignment, also known as molecular orientation, into such a structure. Conversely, numerous methods exist for inducing molecular orientation and thereby enhanced strength into fibrous or expanded node and fibril structures. However, three dimensional fibrous webs cannot be readily produced without the use of either adhesives, adhesive adjuncts, or compression, two of which are processes which inherently reduces the loft of the web leading to more web density and a consequential reduction in the potential for tissue integration. Besides introducing an ongoing risk of dissimilar degradation profiles, the use of an additional adhesive to bond between the web's filaments leads to more material present within the web resulting in decreased void space and an increased mass that delivers the expectation of a proportionally more reactive tissue response upon bioresorption.
The construction of a single component non-woven web without the use of binders is commonly achieved through the direct application of heat and pressure to create a localized melting or fusion of the web filaments at fiber crossover points. However, since heating fibers in the solid state can deliver only limited melt viscosity to the bonding interface without damaging overall fiber integrity, such an approach commonly delivers relatively weak inter-fiber attachments when compared with webs utilizing adhesive binders. Also, regardless to the quality of the produced inter-fiber bonds, such compression under heat inherently reduces web loft, therefore increasing the web's apparent or overall density and limiting the relative amount of available open space within the web for tissue ingrowth.
There remains a need for a non-woven implantable bioresorbable material that is composed of a structure formed from a sufficiently homogenous underlying construction that it would provide for bioresorption in a consistent structural manner as the implant degrades. However, current non-woven fabrics, especially those constructed from bioresorbable polymers, do not meet this need. Fibers in web form are typically bonded together at their points of contact by the application of various known binders or binding techniques, many of which also include the application of pressure which in turn reduces the available loft. Further, with increased concentration of binders, fabrics tend to be stiffer.
The use of any external binder also introduces issues of the uniformity of its distribution throughout the web. Additionally, the properties of the entire web become limited to the properties of the binder which gives the web its integrity, also referred to as cohesion. Thus, for example, if a binder with a relatively low melting point is used as a bonding material, the temperature conditions to which the web may be subjected are limited by the melting point of the binder. Additionally, if the binder is weakened or softened by other factors such as moisture, solvents, or various physiological fluids, then the overall integrity of the web can be affected. These problems are overcome by the self-cohering properties of the present invention.
Solvent bonding, where the reinforcing fibers are swelled by solvent in either liquid or vapor form to provide bonding of the web, is not easily controlled and frequently tends to weaken the web's fibers. Furthermore, the intersections at which the filaments are bonded frequently have a swollen appearance and possess alteration of their polymeric organization or crystalline structure with a resulting loss in strength.
Solvent spinning or "dryspinning" is a process where a polymeric material is dissolved within a suitable solvent to produce a viscous solution which is then extruded through a spinnerette. This process has been used to form non-woven webs with filaments which self-adhere at points of contact due to the use of the solvent as a tackifier adhesive adjunct. When the exiting fluid is directed at a rotating mandrel, non-woven tubular constructions are possible and have been utilized as an implantable vascular graft such as the Vascugraft.RTM. polyesterurethane vascular prosthesis manufactured by B. Braun Melsungen AG (Melsungen, Germany). Other descriptions of this or similar solvent spinning processes used to form non-woven medical implants can be found in U.S. Pat. Nos. 4,323,525 and 4,474,630.
Since the utilized solvent essentially plasticizes or lubricates the polymer chains to the point of dissolution, its removal to a concentration level where its presence no longer significantly affects the polymer's physical properties becomes essential. Such a removal process, typically evaporation by heat, constitutes an additional processing step which becomes more difficult to complete as the acceptable or tolerable residual solvent level becomes lower. This residual level of solvent, which in all cases is detectable at some level, carries particular significance in implantable applications where, dependent on the toxicity of the included solvent, its presence may cause a detrimental bioresponse as it diffuses from an implant. This is of a particular concern in with bioresorbable polymers where the produced implant degrades completely and, in many cases, the only solvents which dissolve the polymer are especially toxic. This is particularly the case with hexafluoroisopropanol and the other similarly toxic fluorinated chemicals that are required to dissolve either PGA homopolymers or PGA block copolymers.
Webs can be produced by melt-blowing or spun-bonding. Meltblown webs are produced by entraining melt spun fibers with convergent streams of heated air to produce extremely fine filaments. Melt blown processing has commonly been described as forming discontinuous sub-denier fibers, relatively short filaments that are typically 1 micron or less in diameter. Since melt blown fibers attain their final diameter while in a semi-molten state, no method is available to further enhance molecular orientation within the fibers before they cohesively attach to each other as a web on the collector screen. The net result is a web of short fibers with low to moderate strength when compared with other fibrous non-woven constructions.
Fabrication of the fibers of spunbond non-wovens is accomplished through entrainment of melt spun fibers followed by subsequent cooling and attenuation utilizing air or mechanical methods to induce molecular orientation or alignment into the resulting continuous filaments. The resulting fibers are generally in the range of 15 micron to 25 micron in diameter. Consequently, spunbond webs are made of continuous fibers or filaments that are generally greater than 10 micron in median diameter. Spunbond processes, however, are generally recognized as requiring a separate bonding step (thus the term spunbond) which interlocks the heretofore unattached fibers. Methods of spunbond interlocking generally utilize either thermal fusion, mechanical entanglement, chemical binders or adhesives, or combinations thereof. However the continuous layering of the drawn spunbond fibers on top of one another causes the surface layer of fibers to have limited integration with lower layers, resulting in an increased ability for the web to lose fibers or fray if the interfiber adhesion is overcome. It is common to compensate for this low web cohesive strength by thermally fusing the web's fibers at intermittent points. However, this heat and pressure process, known as point bonding or thermofusion, virtually eliminates web porosity within the fused areas.
An autogenous self-bonding web made without any requirement for ensuing compression is described in Yung U.S. Pat. No. 4,163,819. The self-cohering properties of the fibers of the produced web are described as being dependent on reduced crystallization dependent on the presence of a polyhydric alcohol (polyol) sequence contained in a block terpolymer. Such polyols are known to readily hydrate and the disclosure describes prevention of crystallization and the enhancement of fiber tackiness when the polymer system is exposed to water. No provision was made for autogenous sel-bonding or self-cohering non-woven webs from polymer systems that could not be classified as polyols. Neither the polymers that were utilized nor the produced articles were described as being useful in an implantable application, nor is the utilized polymer systems considered as bioresorbable. Also, no description of enhanced cohesive or peel strength within the produced web could be identified.
Eschewy, U.S. Pat. No. 5,466,517 assigned to Freudenberg, describes a self bonding web made from biodegradable polycaprolactone homopolymer and blends. Biodegradable in this patent is meant to be degradable by bacteria and microorganisms in soil. The webs described were self cohering and possessed an area density of less than 120 g/m.sup.2. Such a low web density with this particular polymer is likely to result in a web with relatively low tensile and cohesive strength, values not reported within the disclosure. Additionally, the 40-50.degree. C. heated air used in producing the described self-bonding web remains sufficiently close to the 60.degree. C. melting point of the polycaprolactone homopolymer that interfiber attachment or bonding while in a melted condition is likely. Additionally, the fact that Eschewy describes self-bonding webs of polycaprolactone homopolymer demonstrates that microphase separation, a feature of the current invention, is not present since the phenomenon of microphase separation between dissimilar segmental compositions is not possible within a homopolymer system.
It is this inherent limitation of homogenous semicrystalline polymer systems requiring interfiber bonding prior to solidification from the melt that the current invention intends to overcome. In such homopolymer systems, the ability of continuous filament web fibers to contact and self-cohere to themselves must be accomplished before solidification of the filaments from the melt. Since polymer solidification is a function of temperature, the external boundaries of the fibers are the first to cool and, as a consequence, the first to solidify. This rapid solidification of the fibers' outer boundaries functionally diminishes the possibility of creating inter-fiber attachments with later contacting fibers. It is the intention of the present invention to overcome this limitation of requiring interfiber contact prior to solidification and to functionally achieve the goal of delivering a self-cohering continuous filament web where interfiber attachments are formed after the polymeric components have solidified.